Sleepapneaisassociatedwithautonomic,cardiovascular,metabolicandcognitiveco?morbidities.The incidenceofsleepapneaintheUnitedStatesrangesfrom2?4%inthegeneralpopulation,andisupto15times greaterinindividualswithspinalcordinjury(SCI).Adjustmentsintheneuralmodulationofthearousal threshold(AT),chemoreflexsensitivitytohypoxiaandhypercapnia(CS)andupperairwaypatencyarethree criticalfactorsthatcontributetoexacerbationofsleepapnea.Theexactneuromodulatorsthatcontrolthese variablesareenigmatic,butonepossibilityisserotonin(5HT)anditstargetreceptors.Thus,plasticityof5HT neuronsmayaccountformodificationsintheAT,CS,upperairwaypatencyandultimatelybreathingstability inintactandspinalcordinjured(SCI)animals.Wewillexploretheroleof5HTinmodulatingthecritical factorsthatexacerbatesleepapneainintactandSCImice.Aim1ofourproposalwillexaminetheimpactof 5HTontheATandCStoultimatelydeterminetheimpactonsleepdisorderedbreathing.Aim2willexplore whethermodificationsin5HTlevelsand/orreceptorsub?typesfollowingSCI,arecoupledtomodificationsin theATandCSleadingtohypoventilation,bluntingofupperairwaymusclefunctionandincreasesinthe frequencyanddurationofapneaevents.Aim3willdeterminewhethermodificationsin5HTlevelsand/or receptorsub?typesfollowingSCI,arecoupledtoincreasesinupperairwaycollapsibility.Toexplorethese relationshipsunanesthetized,spontaneouslybreathingintactandSCItryptophanhydroxylase2knockout (TPH2?/?)andwildtype(TPH2+/+)micewillbeemployed.TheabsenceofTPH2resultsinthedepletionof centralnervoussystem5HT,whiletherapheneuronsremainintact.Wewillmeasureventilatoryparameters, theATandCSbeforeandafterSCIinTPH2+/+andTPH2?/?mice.Breathingeventswillbedetectedduringsleep viaelectroencephalograms.Apneiceventswillbeuncoveredbymonitoringventilationanddiaphragmatic electromyography,whilemonitoringofgenioglossusmuscleactivitywillbeusedtodetectmodificationsin upperairwaymusclefunctionbeforeandafterSCI.Ourresultswillestablishifmodificationsin5HT modulation,eitherviageneticdepletionorSCI,leadstoalterationsintheAT,CS,upperairwaymuscle functionandultimatelybreathingstability.